This case is related to U.S. Ser. No. 07/991,164, filed Dec. 16, 1992; Merck cases 19043 and 19060.
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is reverse transcription of the RNA genome by a virally encoded reverse transcriptase to generate DNA copies of HIV sequences, a required step in viral replication. It is known that some compounds are reverse transcriptase inhibitors and are effective agents in the treatment of AIDS and similar diseases, e.g., azidothymidine or AZT.
This invention relates to an improved process for synthesizing the AIDS antiviral L-738,372, which is a chiral compound of the following chemical structure, 10: ##STR1##
The substituted quinazoline L-738,372 is an exceptionally potent inhibitor of HIV reverse transcriptase. This activity of the compound makes it useful in the treatment or prevention of AIDS. The present invention describes an improved synthesis of this compound.
The present invention describes the novel reaction of an acetylide with a cyclic N-acylated ketimine. There is a general lack of literature precedent on the asymmetric addition of acetylide nucleophiles, especially to imine derivatives as in the present invention.
The only related chiral acetylide additions have been to aldehydes. Mukaiyama (Chemistry Letters, 447(1979)) reported the addition of acetylides to aldehyde substrates in the presence of a diamine chiral modifier. The asymmetric addition of dialkynylzinc reagents to aldehydes in modest enantiomeric excess has been disclosed by Soai (Journal of the Chemical Society, Perkin Transactions 1,937(1990)). Recently, Corey reported the asymmetric addition of acetylides to aldehydes, catalyzed by chiral oxazaborolidines (Abstracts, 33rd National Organic Chemistry Symposium, June 13-17, 1993, Bozeman, Montana, FIG. 21 ). In the present invention, the substrate is unique in that an acetylide is added to a cyclic N-acylated ketimine rather than a simple aldehyde.
Tomioka [Tetrahedron Letters, 32, 3095(1991); Tetrahedron Letters 31,6681 (1990); Synthesis, 541 (1990)] reports the chiral addition of alkyl and vinyl lithiums (but not acetylides) to relatively unhindered, acylic aldimines in the presence of chiral amino ethers. Amino ethers do not function effectively in the present process.
The use of alkaloids (including the cinchona alkaloids quinine and dihydroquinine) in asymmetric synthesis was reviewed by H. Wyberg, "Asymmetric Catalysis by Alkaloids," in E.L. Eliel (Ed.), Topics in Stereochemistry, Vol. 16, Wiley and Sons, pp. 87-129 and by Blaser (Chemistry Reviews, 92, 935(1992)). No precedent for the chiral addition of acetylides to cyclic ketimines is reported.